, Volume 20, Issue 2, pp 233–241 | Cite as

Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

  • MariaRosa Bani
  • Alessandra Decio
  • Raffaella Giavazzi
  • Carmen Ghilardi
Original Paper


Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.


Tumor endothelial cells Drug resistance P-glycoprotein Tyrosine kinase inhibitor Angiogenesis Ovarian adenocarcinoma 



We are grateful to Sara Figini for technical support and to Viviana Rossi for assistance in manuscript preparation.


This study was supported by a Grant from the Italian Association for Cancer Research (AIRC No. 12182 and IG No. 18853 to RG).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with ethical standards of the institution or practice at which the studies were conducted.


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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • MariaRosa Bani
    • 1
  • Alessandra Decio
    • 1
  • Raffaella Giavazzi
    • 1
  • Carmen Ghilardi
    • 1
  1. 1.Laboratory of Biology and Treatment of MetastasisIRCCS-Mario Negri Institute for Pharmacological ResearchMilanItaly

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